Novel process for coating inhalation devices

ABSTRACT

The invention relates to coating inhalation devices and their components by cold plasma (pulsed or continuous wave) with fluorinated acrylates. The process gives inhalation devices with improved product performance by reducing drug deposition on the coated parts.

FIELD OF THE INVENTION

This invention describes how cold plasma coating can be used to improvethe performance of inhalation devices. In particular, it describes theuse of fluorinated acrylate molecules to reduce drug adhesion to devicecomponents. These compounds conjointly with the way they are graftedonto surfaces are new to the area of inhalation devices. This inventioncan be applied to a range of surfaces (metals, plastics) and used with arange of drug molecules for the treatment of local conditions (mouth,lung, nose, throat and lung diseases). It can also be used in thesystemic treatment a wide range of ailments (lung cancer, migraine,diabetes etc . . . ).

BACKGROUND OF THE INVENTION

Inhalation treatments of a series of medical conditions rely onsophisticated devices to deliver the drug to the desired target. Thesedevices can themselves introduce new variables in the optimisation ofthe product performance. These are mainly due to drug adsorption to theelements constituting the device. For example, the device can be a pMDIused in the treatment of respiratory diseases. A pMDI is made up of acanister, an actuator and a complex valve assembly. All the componentsof this pMDI are potential sites of drug adhesion, therefore loss ofdrug leading to irregular dosing. Reducing drug adhesion is of primaryimportance for the design of a robust product. This can be achieved bymodifying the drug formulation or the surface properties of the devicecomponents.

The problem is particularly acute in pMDI. The requirement to use HFApropellants, for the treatment of asthma for instance, imposed by theMontreal protocol has led to a series of unexpected hurdles in thedevelopment of new products. This is mostly due to the characteristicsof the liquid HFA and the behaviour of the drug suspensions preparedwith them. HFA propellants have very low surface tensions and wet solidsurfaces with remarkable efficiency. This means that due to capillaryforces, the propellants spread up can walls very easily, and leave athin film of caked particles. Furthermore, because of the poor solventproperties of the propellants, drug particles have a tendency to move tothe propellant/device interface to have a more energetically favourablecontact than they would by remaining in the bulk. Both phenomenon can bereduced by coating the device and its components with appropriatechemicals. A range of coatings can be applied in a variety of fashionwith a varying degree of success.

One of the early forms of coating is spray coating. It is a process akinto painting and is used successfully in the food and paint industry. Forexample PCT/SE/01/01606 discloses the spray coating of fluorinatedalkylpolyglycosides. Most spray coating methods suffer from the drawbackto rely on multiple steps processes. The can has to be sprayed and driedbefore use. Anodisation of the aluminium parts is often required aswell. The uniformity and integrity of such coating can be an issue,since spray guns cannot access the intricate details of some componentsdesign. Finally, the coating layer thus deposited can be scraped off thesurface, and introduces leachables and unwanted chemicals in themedicament composition.

Silanisation is another way of modifying surface properties. For examplePCT/SE/01/12749 indicates how such treatment can be used to reduce drugadhesion. This treatment is a solvent based method and require the cansto be washed after treatment and tested for cleanliness before being putto use for medical treatment.

Plasma coating is known in the art, for example WO 99/64662 and WO00/05000 disclose plasma coating of a surface such as a fabric. GB 2 355252 discloses plasma coating of a medicinal device with certain siliconbased polymers. However Fluorinated acrylates are not disclosed norsuggested.

Reducing the attraction between drug particles and solid surfaces willlead to a reduce particle adhesion, since the particles will not reachthe surfaces.

SUMMARY OF THE INVENTION

It has been found that drug adhesion to the elements (i.e. can, stem,valves, seals etc . . . ) of inhalation devices (nasal, nebulisers,pMDIs, DPIs . . . ) can be dramatically reduced by coating theseelements by cold plasma with fluorinated acrylates. The process caneither be pulsed or continuous. Some or all of the above components canbe coated using the processes of the invention.

In a first aspect, the invention provides a device for dispensing a drugby inhalation wherein the device or components thereof are coated by acold plasma coating process characterised in that the coating is afluorinated acrylate compound or a mixture thereof.

In a further aspect, the invention provides use of a fluorinatedacrylate compound for the cold plasma coating of a medicinal device.

In a further aspect, the invention provides a process for coating amedicinal device with a fluorinated acrylate which comprises coating thedevice with a cold plasma.

The term “cold plasma” means that the temperature within the body of theplasma is ambient.

The advantages of the invention are that no spray guns are used for thecoating. Henceforth, problems associated with conventional coatingmethods such as spray blockage can be avoided. In addition since thepresent invention employs cold plasma, polymers can be used that couldnot otherwise be used with conventional spraying such as unstablepolymers The medicinal devices can be coated in a batch process. Coldplasma is also better than standard coating in that a more uniform coatis achieved and the coating can reach in the intricate part of thedevice design that standard spray coating fails to reach. Finally, achemical bond is achieved between substracte and coating, which providesa longer lasting and more efficient coated layer.

The chemicals with which the device components can be coated arefluorinated acrylates suitable for plasma coating. Short chain acrylatesare preferred. The molecules can be straight of branched chains. Mostpreferably 1H, 1H, 2H, 2H heptadecafluorodecyl acrylate, 1H, 1H, 2H, 2Hperfluoroctyl acrylate and 1H, 1H, 2H, 2H perfluoroctyl methacrylate canbe used. Any other homologous compound in the acrylate family can alsobe used. This list does not pretend to be exhaustive, and any personskilled in the art could identify other compounds with similarstructures as being covered in this invention. These would includehomologous series of the previous molecules (i.e. with a varying chainlength, or branching), and other straight chain fluorinated acrylatesand methacrylates. Chain length less than 25 carbon atoms long arepreferred, most preferably they should have less than 20 carbon atoms,most most preferably less than and including 16.

The thickness of the coated layer can range from 1 nm to 500 μmPreferably between 5 nm and 100 μm.

The invention can be applied successfully to any part of an inhalationdevice where drug adhesion can occur. For pMDIs, the actuator, the stem,the valve components, the measuring chamber, the seals, and the canistercan all be treated. The invention relates to inhalation therapytherefore includes also nebulisers, nasal sprays and dry powder inhalers(DPI's).

The invention is particularly successful with drugs suitable for theinhaled route. Examples of specific drugs which can be used according tothe invention include mometasone, ipratropium bromide, tiotropium andsalts thereof, salemeterol, fluticasone propionate, beclomethasonedipropionate, reproterol, clenbuterol, rofleponide and salts,nedocromil, sodium cromoglycate, flunisolide, budesonide, formoterolfumarate dihydrate, Symbicort™ (budesonide and formoterol),3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(4-methylphenyl)ethoxy)ethyl]propansulphonamide,terbutaline, terbutaline sulphate, salbutamol base and sulphate,fenoterol,3-[2-(4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-[24-methylphenyl)ethoxy]ethyl]propanesulphonamide,hydrochloride. All of the above compounds can be in free base form or aspharmaceutically acceptable salts as known in the art.

The coating process can be carried out using the techniques described inWO 99/64662 and WO 00/05000.

The full potential of this invention is revealed for particles with asize distribution between 100 nm and 1000 μm, most preferably between500 nm and 500 μm, even more preferably between 900 nm and 100 μm, mostpreferably between 900 n=and 30 μm.

The invention works particularly well when the particles are dispersedin a non-aqueous pressurised medium such as the propellants HFA227 andBFA134a, or any mixture thereof. The invention can also be appliedsuccessfully to devices having formulations with HFA propellants, orpropellant mixtures to which have been added polymers or co-solvents.

The invention is illustrated by the following examples.

EXAMPLES

To assess the usefulness of the coating technique for inhalation aseries of tests were performed. Aluminium surfaces were coated with 3types of polymers under 2 types of conditions. Interactions between drugparticles and the treated surfaces were then measured by Atomic ForceMicroscopy (also known as AFM). The strength and range of theseinteractions were compared with the ones obtained from an uncoatedsurface.

The materials used to exemplify the invention were: 1H, 1H, 2H, 2HHeptadecafluorodecyl acrylate, 1H, 1H, 2H, 2H Perfluoroctyl Acrylate and1H, 1H, 2H, 2H Perfluoroctyl Methacrylate.

The chemicals were cold plasma coated onto aluminium sheets. TheseAluminium surfaces are the one currently used to manufacture pMDIcanisters. With 3 different chemicals and 2 methods of production, atotal of 6 coatings were investigated. In addition, an anodisedaluminium surface and a non-anodised one were studied to provide areference for the interactions.

The drug used in these tests was formoterol fumarate dihydrate(abbreviated as FFD). Its size distribution was centred around 2 μm.

The extent of the adhesion between the particles and the treatedsurfaces was tested in a fluorinated solvent, 2H, 3H perfluoropentane(abbreviated as HPFP). This liquid is a very good substitute for bothpropellants HFA227 and BFA134a. It is used when tests can not beperformed in situ in pressurised liquids, such as AFM.

Substrate surfaces were imaged in air with a Digital InstrumentsNanoscope III AFM in TappingMode™ operation, using standard silicon TBSPcantilevers (Nanoprobes, Digital Instruments, Santa Barbara). Typicalscan rates for all images were between 1-1.5 Hz with a pixel resolutionof 512×512. Force-distance interactions and force volume data wererecorded under in-situ conditions, via a hermetically sealed contactmode in-situ cell (Digital Instruments, Santa Barbara). Drug particleswere glued on a tipless cantilever to act as a colloidal probe.

The adhesion force was calculated from the retracting force-distancecurve. The adhesion energy is the product of the maximum force by thedistance to which the cantilever retracts when going away from thesurface (see FIG. 1, do you have the figure, they should have been sentwith the previous e-mail???). The AFM technique used in this studyrecords a series of force-distance curves on a finite surface and foreach points calculates an adhesion energy. When a repulsion is felt, nocalculation is possible. The energy values quoted are average valuesover a finite element of the surface (on average 20 μm×20 μm).

Reference Sample: Non Anodised Aluminium Surface:

A non anodised aluminium surface was used as a reference. The forcedistance curve for this sample can be found on FIG. 2.

An attractive force was felt on approaching the surface. The attractiveforce led to an adhesion force on contact of ˜8 nN. For each pointmeasured an adhesion energy was calculated from the retractionexperiment (i.e. when the cantilever is taken away from the surface).The adhesion energy spread can be found on FIG. 3. Because of theroughness of the surface, the adhesion energy spreads over a range ofenergy values. Two areas of adhesion are seen: a low adhesion centredaround 5.8 nJ and a high adhesion region centred on 36.4 nJ. The energyspread is due to the variations in surface roughness.

Reference Sample: Anodised Aluminium Surfaces:

A second reference sample was studied. This was an anodised aluminiumsurface. Anodised aluminium sheets are also used in the process ofmaking pMDI canisters.

As with the previous sample, an attractive force was felt on approachingthe drug particle to the surface. This attractive force was translatedinto and adhesive force on contact for which an adhesive energy can becalculated. The adhesion force was on average 51.5 nN, yielding adhesionenergies between 5 and 1500 nJ. (see FIG. 4 for energy diagram). Thehigh adhesion energies are centred on 1038 nJ.

Sample 1: Aluminium Surface Cold Plasma Coated with 1H, 1H, 2H. 2Hheptadecafluorodecyl acrylate with a Continuous Wave.

As can be seen from the force-distance profile for this sample (see FIG.5), no attractive force was detected on approaching the particle to thecoated surface.

There was however a weak and irregular adhesion force on retraction.Probably due to some drag caused by the extension of the fluorinatedchain. The drug and cantilever on retraction dragged the chain with themand created what appears to be an attractive force. This force howeveris mechanical in nature, and is not of the van der Waals type. i.e. itsextent stops where the molecular chain finishes, it is a contact force.The system was essentially non attractive and no adhesion energy couldbe calculated.

The plasma coating is therefore an effective way of reducing particleadhesion.

Sample 2: Aluminium Surface Cold Plasma Coated with 1H, 1H, 2H, 2Hheptadecafluorodecyl acrylate with a Pulsed Wave.

The same observation were done on this sample as on sample 1. Noattraction is detected, and an irregular adhesion is seen.

Therefore, the 1H, 1H, 2H, 2H heptadecafluorodecyl acrylate coating,either applied as a continuous wave or a pulsed one, is an effectivehindrance to particle adhesion to surfaces in a fluorinated environment.

Sample 3: Aluminium Surface Cold Plasma Coated with 1H, 1H, 2H, 2Hperfluoroctyl acrylate with a Continuous Wave.

No attraction was detected on approaching the particle to the coatedsurface. On retraction, no adhesion was observed.

This coating is a very effective way of preventing drug adhesion.

Sample 4: Aluminium Surface Cold Plasma Coated with 1H, 1H, 2H, 2Hperfluoroctyl acrylate with a Pulsed Wave.

No attraction was detected on approaching the particle to the coatedsurface. On retraction, no adhesion was observed.

This coating is a very effective way of preventing drug adhesion.

Sample 5: Aluminium Surface Cold plasma coated with 1H, 1H, 2H, 2Hperfluoroctyl methacrylate with a Continuous Wave.

No attraction was detected on approaching the particle to the coatedsurface. On retraction, no adhesion was observed.

This coating is a very effective way of preventing drug adhesion.

Sample 6: Aluminium Surface Cold Plasma Coated with 1H, 1H, 2H, 2Hperfluoroctyl methacrylate with a Plused Wave.

No attraction was detected on approaching the particle to the coatedsurface. On retraction, no adhesion was observed.

This coating is a very effective way of preventing drug adhesion.

FIG. 6 summarises the average energies for all samples. No adhesionenergy could be calculated for any of the coated samples, whereasuncoated samples had strong adhesive energies and attractive forces.

LIST OF FIGURES

FIG. 1: Calculation of adhesion energy from AFM measurements.

FIG. 2: Force vs distance curve for FFD against a non anodised aluminiumsurface in HPFP.

FIG. 3: Energy map for the interaction between FFD and a non anodisedaluminium surface in HPFP.

FIG. 4: Energy map for the interaction between FFD and an anodisedaluminium surface in HPFP.

FIG. 5: Force vs distance curve for FFD against the surface of sample 1in HPFP.

FIG. 6: Summary of adhesion energies for coated and uncoated samples.

1. An device for dispensing a drug by inhalation wherein the device orcomponents thereof are coated by a cold plasma coating processcharacterized in that the coating is a fluorinated acrylate compound ora mixture thereof.
 2. A device according to claim 1 in which thefluorinated acrylate compound is 1H, 1H, 2H, 2H heptadecafluorodecylacrylate, 1H, 1H, 2H, 2H perfluoroctyl acrylate or 1H, 1H, 2H, 2Hperfluoroctyl methacrylate.
 3. A device according to claim 1 in whichthe can is coated.
 4. A device according to claim 1 in which the stem iscoated.
 5. A device according to claim 1 in which the actuator iscoated.
 6. A device according to claim 1 in which the seals are coated.7. A device according to claim 1 in which the drug is mometasone,ipratropium bromide, tiotropium and salts thereof, salemeterol,fluticasone propionate, beclomethasone dipropionate, reproterol,clenbuterol, rofleponide and salts, nedocromil, sodium cromoglycate,flunisolide, budesonide, formoterol fumarate dihydrate, Symbicort™(budesonide and formoterol),3-[2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(4-methylphenyl)ethoxy)ethyl]propansulphonamide,terbutaline, terbutaline sulphate, salbutamol base and sulphate,fenoterol,3-[2-(4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethylamino]-N-[2-[2-(4-methylphenyl)ethoxy]ethyl]propanesulphonamide,hydrochloride.
 8. The use of a fluorinated acrylate compound for thecold plasma coating of a medicinal device.
 9. A process for coating amedicinal device with a fluorinated acrylate which comprises coating thedevice using a cold plasma.